It has been estimated that expression of at least 30% of mammalian protein-encoding genes is regulated, to some extent, by microRNAs (miRNAs) via the RNAi pathway. We have used our expertise and knowledge, based on exploitation of the RNAi mechanism, to develop research focused on the regulation of normal- and cancer-associated gene expression by miRNAs. MicroRNAs are expressed as primary miRNA transcripts that undergo multi-step enzymatic processing to generate the mature form via a precursor intermediate. miRNAs exert their effect on endogenous gene expression through the formation of a ribonucleoprotein complex that uses the miRNA as a guide for the alignment of the complex with a transcript. Determination of the molecular mechanism(s) by which miRNAs modulate protein expression is the subject of intense study. As yet no consensus model has emerged to explain all the proposed facets of miRNA-mediated gene regulation. Although miRNA-induced cleavage and degradation of a target mRNA has been reported, translational repression is currently the favored model of miRNA-mediated gene silencing in mammalian cells. A variety of biological processes have been implicated as being regulated by miRNAs, including cell development, differentiation, proliferation, and metabolism. The involvement of miRNAs in human disease has been particularly focused in cancer biology. Our research studies are focused on the hypothesis that the regulation of gene expression by miRNAs is altered in cancer. For example, we recently established that the receptor tyrosine kinase AXL as a functionally relevant target of the p53 regulated miRNA, miR-34a, in breast cancer. We have also identified miRNAs within a region (8q24) associated with genomic instability that includes the long non-coding RNA (lincRNA), PVT1, 3? of the proto-oncogene MYC. These small non-coding RNA species have been annotated as microRNAs (miR-1204-1208) and we, and others, have shown that at least some of these are functionally active and that at least one, miR-1204, is responsive to regulation by p53. Current research is focused on examining the over-expression of miR-1204 in a panel of mouse cell lines representing evolving stages of B cell development and in several mouse models of cancer to determine what role this miRNA may play in normal B cell development or lymphomagenesis. We have also over-expressed miR-12041208 in prostate cell lines in an attempt to reconstitute the over-expression and amplification of genes found in the 8q24 region in many epithelial malignancies including prostate, breast, colon and pancreatic carcinoma. As a follow-up to the discovery of miR-12041208 in the 8q24 region, we have analyzed the overall genomic distribution of miRNAs in relationship to known markers of genomic instability particularly retroviral integration sites associated with mouse models of cancer. The recent discovery that some of the miRNAs such as miR-1206 and miR-1207-5p have sequence variants have also led us to begin to analyze how variation may alter the expression or processing of miRNAs and related regulatory RNAs.